2-Amino-5-bromomethyl-3-cyanopyrazine

The isonipecotinoyl analogues of FA and AP, (592) and (593) respectively, were prepared from 2-amino-5-bromomethyl-3-cyanopyrazine (16b) by an extension of the strategy first developed by Taylor, as depicted in Scheme 3.123 [2491. 

Amino-5-bromomethyl-3-cyanopyrazine with the sodium salt of diethyl malonate in tetrahydrofuran at room temperature gave 2-amino-3-cyano-5-(2, 2 -diethoxycarbonylethyl)pyrazine together with a little dialkylated product (1031). Similar reactions were observed with the sodium salts of ethyl acetoacetate and ethyl 7-ethoxyacetoacetate, but methyl cyanoacetate gave only dialkylated product (1031). 2-Amino-5-chloromethyl-3-cyanopyrazine and 1-pyrroIidino-l-cyclohexene in tetrahydrofuran have been shown to give 2-amino-3-cyano-5-(2 -oxocyclohexyl-methyOpyrazine (542). 

Chloromethylpyrazine with sodium azide in refluxing aqueous acetonitrile gave 2-azidomethylpyrazine (690), and 2-amino-5-bromomethyl-3-cyanopyrazine with sodium cyanide in dimethyl sulfoxide at 40° gave 2-amino-3-cyano-5-cyano-methylpy razine (1031). 

Condensation of 2-amino-5-bromomethyl-3-cyanopyrazine 1-oxides with the appropriate substituted amine afforded a series of 2-amino-5-([(aryl and aralkyl)-amino]methyl -3-cyanopyrazine 1-oxides (1040), and with p-chlorophenol and arylthiols gave 2-amino-5-[(p-chlorophenoxy)methyl]-3-cyanopyrazine 1-oxide and 2-amino-5[(arylthio)methyl]-3-cyanopyrazine 1-oxides (1041). 

Amino-5-bromomethyl-3-cyanopyrazine with ethyl acetoacetate and sodium hydride in tetrahydrofuran gave 5-[(2 -acetyl-2 -ethoxycarbonyl)ethyl]-2-amino-3-cyanopyrazine (1031) [which with sodium chloride in aqueous dimethyl sulfoxide at 155-170° for 6 hours gave 5-(2 -acetylethyl)-2-amino-3-cyanopyrazine] and a similar reaction with ethyl y-ethoxyacetoacetate gave 2-amino-3-cyano-5-[(2 -ethoxycarbonyl-2 -ethoxymethylcarbonyl)ethyl]pyrazine [which with sodium chloride in aqueous dimethyl sulfoxide at 155-170° for 6 hours gave 2-amino-3-cyano-5-(2 -ethoxymethylcarbonyl)ethylpyrazine] (1031). 

Amino-5-chloromethyl-3-cyanopyrazine 1-oxide with triphenylphosphine in dimethylformamide at 80-90° gave 2-amino-3-cyano-5-(triphenylphosphonio)-methylpyrazine 1-oxide chloride (97) (520) and the 5-bromomethyl analogue reacted similarly with triphenylphosphine in propan-2-ol (542). Compound (97) on hydrolysis with 30% aqueous ethanol containing a small amount of triethylamine gave 2-amino-3-cyano-5-methylpyrazine 1-oxide and thus enabled removal of the chloro substituent from the chloromethylpyrazine (529) compound (97) with triethylamine and acetaldehyde (and other aldehydes) in chloroform at room temperature gave 2-amino-3-cyano-5-(prop-l -enyl)pyrazine 1-oxide (and other alkenyl analogues) (529). 

---